The overall objective of this project is to define more clearly the role of insulin and cyclic 3'5'-nucleotides in the regulation of polymorphonuclear leukocytes, thymus-dependent lymphocytes and macrophages. Subpopulations of thymus-dependent lymphocytes obtained by passing spleen cells over nylon wool columns will be studied using cells from normal and genetically obese mice as well as normal and alloxan-diabetic rats. The responsiveness of cells to mitogens, allogeneic cells, and agents that alter cyclic nucleotides will be compared. These experiments are designed to see if the apparent decreased responsiveness of diabetic cells is associated with a change in cyclic AMP or cyclic GMP metabolism. Macrophages will be studied using a macrophage tumor live to see if insulin directly affects glucose uptake, glycogen metabolism, cyclic nucleotide levels, and the activation of macrophages by endotoxins and lymphokines. Human neutrophils from normal and diabetic patients will be compared in terms of cyclic nucleotide metabolism, chemotaxis, and lysosomal enzyme release in the presence of various concentrations of insulin in vitro. BIBLIOGRAPHIC REFERENCES: Pallavicini, M.G. and Nichols, W.K., Inhibition of lymphocyte blastogenesis by factor(s) in alloxan-diabetic rat plasma. Diabetes 25: 614-622, 1976. Nichols, W.K., Changes in cyclic AMP accumulation of mononuclear leukocytes from alloxan-diabetic rats. Fed. Proc. 35:609, 1976.